A typical human being is about 60 percent water, and in the free fall of space, the body’s fluids float upward, into the chest and the head. Legs atrophy, faces puff, and pressure inside the skull rises.

“Your head actually feels bloated,” said Mark E. Kelly, a retired NASA astronaut who flew on four space shuttle missions. “It kind of feels like you would feel if you hung upside down for a couple of minutes.”

The human body did not evolve to live in space. And how that alien environment changes the body is not a simple problem, nor is it easily solved.

Some problems, like the brittling of bone, may have been overcome already. Others have been identified — for example, astronauts have trouble eating and sleeping enough — and NASA is working to understand and solve them.

Then there are the health problems that still elude doctors more than 50 years after the first spaceflight. In a finding just five years ago, the eyeballs of at least some astronauts became somewhat squashed.

The biggest hurdle remains radiation. Without the protective cocoon of Earth’s magnetic field and atmosphere, astronauts receive substantially higher doses of radiation, heightening the chances that they will die of cancer. How much of a cancer risk later in life is acceptable?

At the Johnson Space Center here, the home base for NASA’s human spaceflight program, scientists probably have until the 2030s to dissect these problems before the agency sends astronauts to Mars — a mission that would take about 2.5 years, or nearly six times the current standard tour of duty on the space station.

The longest any human has been off Earth is almost 438 days, by Dr. Valery Polyakov on the Russian space station Mir in 1994 and 1995. (Two private organizations, Inspiration Mars and Mars One, have announced plans to launch a manned interplanetary flight sooner and have had no problem attracting people despite the risks, known and unknown.)

NASA officials often talk about the “unknown unknowns” — the unforeseen problems that catch them by surprise. The eye issue caught them by surprise, and they are happy it did not happen in the middle of a mission to Mars.

In 2009, during his six-month stay on the International Space Station, Dr. Michael R. Barratt, a NASA astronaut who is also a physician, noticed he was having some trouble seeing things close up, as did another member of the six-member crew, Dr. Robert B. Thirsk, a Canadian astronaut who is also a doctor. So the two performed eye exams on each other, confirming the vision shift toward farsightedness.

They also saw hints of swelling in their optic nerves and blemishes on their retinas. On the next cargo ship, NASA sent up a high-resolution camera so that they could take clearer images of their eyes, which confirmed the suspicions. Ultrasound images showed that their eyes had become somewhat squeezed.

NASA is now checking astronauts’ eyesight before, during and after trips to the space station.

The issue turns out not to be new. Many space shuttle astronauts had complained of changes in eyesight, but no one had studied the matter.

“It is now a recognized occupational hazard of spaceflight,” Dr. Barratt said. “We uncovered something that has been right under our noses forever.”

Dr. Barratt said the vision shift had no effect on his ability to work in space. The concern, however, is that the farsightedness may be just a symptom of more serious changes in the astronauts’ health. “What are the long-term implications?” he said. “That’s the $64 million question.”

It is one of the many things NASA will be monitoring in the health of Scott J. Kelly, who will spend one year on the space station beginning in spring 2015: twice as long as his stay there in 2010 and 2011 and the longest for an American. A Russian astronaut, Mikhail Kornienko, will also make a yearlong trip to orbit then. Dr. Polyakov and three other Russian astronauts have already had orbital stays longer than that and returned seemingly not much the worse for wear.

John B. Charles, chief of the international science office of NASA’s human research program, is setting up the medical experiments, designed to figure out whether there are differences between a six-month stay and a 12-month stay. “Logically, you might say, how can there not be?” Dr. Charles said.

But it is also possible that the body becomes acclimated to weightlessness after only a few months, and that the changes in vision and bones level off.

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An astronaut's eyeball before a spaceflight, top left, and after a flight, top right, showing pressure against the back of the eyeball. In the bottom image, the arrows point to abnormal bends in the optic nerve following spaceflight.CreditRadiological Society of North America

The doctors will also compare Scott Kelly’s health with that of Mark Kelly, his twin brother. “I imagine I’ll be giving blood and urine samples,” said Mark Kelly, who is married to Gabrielle Giffords, the former Arizona congresswoman. “My attitude is, I worked at NASA for 16 years and whatever I can do to help, I will.”

A decade ago, NASA scientists worried that astronauts were returning to Earth with weaker bones, their density draining away by 1 to 2 percent per month. In space, the body does not need to support its weight, and it responds by dismantling bone tissue much faster than on Earth.

NASA turned to osteoporosis drugs and improved exercises, like having the astronauts run while strapped to a treadmill. The up-and-down pounding set off signals to the body to build new bone, and NASA scientists reported that astronauts then came back with almost as much bone as when they had left.

Because both the formation and destruction occur at accelerated rates, “we don’t know if that bone is as strong as when you left,” Dr. Smith said. But the scientists now feel that bone loss is not a showstopper for a long-duration mission.

For the eyesight issues, scientists have more questions than answers. They suspect that the adverse effects result largely from the fluid shift, the higher pressure of the cerebrospinal fluid in the skull pushing on the back of the eyeballs, but that has not been proved. And that theory does not explain why it usually affects the right eye more than the left, and men far more than women.

Dr. Smith has also found that the astronauts who experienced a shift in vision had increased levels of the amino acid homocysteine, often a marker for cardiovascular disease. That may suggest that a zero-gravity environment sets some biochemical process in motion.

Artificial gravity could be generated by spinning the spacecraft like a merry-go-round, alleviating both the bone loss and the fluid shift. But that would also add complexity to a mission and raise the potential for a catastrophic accident.

But the eye issue “could be something that drives us back to artificial gravity,” Dr. Barratt said.

The lack of gravity also jumbles the body’s neurovestibular system that tells people which way is up. When returning to the pull of gravity, astronauts can become dizzy, something that Mark Kelly took note of as he piloted the space shuttle to a landing. “If you tilt your head a little left or right,” he said, “it feels like you’re going end over end.”

That may not be as big an issue for a Mars spacecraft that lands autonomously, and in which the astronauts have time to rest before getting out of their seats.

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Expedition 31 crew members were carried to a medical tent shortly after they landed in their Soyuz capsule in remote Kazakhstan, in 2012.CreditBill Ingalls/NASA

Regarding radiation, NASA operates under a restriction that astronauts should not have their lifetime cancer risk raised by more than three percentage points, but that is an arbitrary limit. Mark Kelly, for one, said he would be willing to accept twice that if he had a chance to go to Mars.

There may be other complications, though. At Brookhaven National Laboratory on Long Island, scientists are bombarding mice with radiation that mimics high-energy cosmic rays that zip through outer space. Those mice take longer to navigate a maze, suggesting that the radiation may be damaging their brains.

Scientists say it may damage other organs, including the heart, nervous system and digestive system. “Those could be acute effects,” said William H. Paloski, the head of NASA’s human research program. “We just don’t know. It’s one we’re looking at.”

Beyond the body, there is also the mind. The first six months of Scott Kelly’s one-year mission are expected to be no different from his first trip to the space station.

But Dr. Gary E. Beven, a NASA psychiatrist, said he was interested in whether anything changed in the next six months. “We’re going to be looking for any significant changes in mood, in sleep, in irritability, in cognition,” he said.

For trips beyond Earth orbit, astronauts will be isolated from the rest of humanity. During the Apollo missions, there was a lag time of 1.3 seconds between a command from mission control and an astronaut’s hearing it, the time for a radio signal to travel the 240,000 miles from Houston to the moon. At Mars, the lags would stretch minutes, and real-time conversation with someone on Earth would be impossible.

The crew of a Mars mission — four or six astronauts in NASA’s current thinking — would have to be more self-reliant to solve any personality conflicts. Dr. Beven envisioned computer systems that could detect subtle changes in facial expressions or tone of voice, perhaps offering some suggestions for defusing tensions.

In a Russian experiment in 2010 and 2011, six men agreed to be sealed up in a mock spaceship simulating a 17-month Mars mission. Four of the six developed disorders, and the crew became less active as the experiment progressed.

“I think that’s just an example of what could potentially happen during a Mars mission, but with much greater consequence,” Dr. Beven said. “Those subtle changes in group cohesion could cause major problems.”

Dr. Charles said he thought NASA could already send astronauts to Mars and bring them back alive. But given the huge expense of such a mission, he said it was crucial that the astronauts arrived productive and in great health.

“My goal,” he said, “is to see a program that doesn’t deliver an astronaut limping to Mars.”